title: Fc epsilon receptor I-associated lyn-dependent phosphorylation of Fc gamma receptor IIB during negative regulation of mast cell activation.
abstract: Fc gamma RIIB are low-affinity receptors for IgG whose intracytoplasmic domain contains an immunoreceptor tyrosine-based inhibition motif (ITIM). Fc gamma RIIB inhibit cell activation triggered by receptors that signal via immunoreceptor tyrosine-based activation motifs. This inhibition requires ITIM tyrosyl phosphorylation and is correlated with the binding of SH2 domain-containing phosphatases that may mediate the inhibitory signal. In the present work, we investigated the mechanism of Fc gamma RIIB phosphorylation and its consequences in mast cells. We demonstrate that the phosphorylation of Fc gamma RIIB requires coaggregation with Fc epsilon RI and that, once phosphorylated, Fc gamma RIIB selectively recruit the inositol polyphosphate 5 phosphatase SHIP, in vivo. In vitro, however, the phosphorylated Fc gamma RIIB ITIM binds not only SHIP, but also the two protein tyrosine phosphatases, SHP-1 and SHP-2. We show that the coaggregation of Fc gamma RIIB with Fc epsilon RI does not prevent Fc epsilon RI-mediated activation of lyn and syk. Both kinases can phosphorylate Fc gamma RIIB in vitro. However, when coaggregated with Fc epsilon RI, Fc gamma RIIB was in vivo phosphorylated in syk-deficient mast cells, but not in lyn-deficient mast cells. When Fc epsilon RI are coaggregated with Fc gamma RIIB by immune complexes, Fc epsilon RI-associated lyn may thus phosphorylate Fc gamma RIIB. By this mechanism, Fc epsilon RI initiate ITIM-dependent inhibition of intracellular propagation of their own signals.
authors.affiliation: Laboratoire d'Immunologie Cellulaire et Clinique, INSERM U.255, Institut Curie, Paris, France.
authors.forename: O
authors.initials: O
authors.lastname: Malbec
authors.forename: D C
authors.initials: DC
authors.lastname: Fong
authors.forename: M
authors.initials: M
authors.lastname: Turner
authors.forename: V L
authors.initials: VL
authors.lastname: Tybulewicz
authors.forename: J C
authors.initials: JC
authors.lastname: Cambier
authors.forename: W H
authors.initials: WH
authors.lastname: Fridman
authors.forename: M
authors.initials: M
authors.lastname: Daëron
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000276:immunology / Q000378:metabolism*; D015536:Down-Regulation / Q000276:immunology*; D004789:Enzyme Activation / Q000276:immunology; D004792:Enzyme Precursors / Q000378:metabolism; D007073:Immunoglobulin E / Q000502:physiology; D047908:Intracellular Signaling Peptides and Proteins; D008407:Mast Cells / Q000201:enzymology* / Q000276:immunology*; D012515:Mast-Cell Sarcoma; D051379:Mice; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases; D010744:Phosphoric Monoester Hydrolases / Q000378:metabolism; D010766:Phosphorylation; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D051381:Rats; D011940:Receptor Aggregation / Q000276:immunology; D017455:Receptors, IgE / Q000276:immunology / Q000378:metabolism*; D017452:Receptors, IgG / Q000276:immunology / Q000378:metabolism*; D054593:SH2 Domain-Containing Protein Tyrosine Phosphatases; D000072377:Syk Kinase; D014407:Tumor Cells, Cultured; D018909:src Homology Domains / Q000276:immunology; D019061:src-Family Kinases / Q000276:immunology / Q000378:metabolism*
chemical_list: D015703:Antigens, CD; D004792:Enzyme Precursors; C080571:Fc gamma receptor IIB; D047908:Intracellular Signaling Peptides and Proteins; D017455:Receptors, IgE; D017452:Receptors, IgG; D007073:Immunoglobulin E; D011505:Protein-Tyrosine Kinases; C000606896:SYK protein, human; D000072377:Syk Kinase; C000606897:Syk protein, mouse; C000606898:Syk protein, rat; D019061:src-Family Kinases; D010744:Phosphoric Monoester Hydrolases; C516724:PTPN11 protein, human; C509249:PTPN6 protein, human; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases; C516725:Ptpn11 protein, mouse; C516727:Ptpn11 protein, rat; C509248:Ptpn6 protein, mouse; C509250:Ptpn6 protein, rat; D054593:SH2 Domain-Containing Protein Tyrosine Phosphatases; C098706:INPPL1 protein, human; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases